1. Cancer Treatment
Despite recent advances in chemotherapy and radiation, cancer remains the second deadliest disease in the United States. There will be nearly two million new cancer cases diagnosed, and more than 525,000 people are expected to die from cancer in 1993. The overall five-year survival approximates fifty percent for all patients, and the prognosis remains particularly poor for those with advanced solid tumors.
2. Effect of Viruses on Cancer
An association between exposure to various viruses and tumor regression has been the subject of several previous case reports. Most of the viruses described in those reports are pathogenic in humans, and include mumps and measles. The effect of other specific viruses on particular types of cancer cells has also been described. Smith et al., (1956) Cancer, 9, 1211 (effect of APC virus on cervix carcinoma); Holzaepfel et al., (1957) Cancer, 10, 577 (effect of APC3 virus on epithelial tumor); Taylor et al., (1970) J. Natl. Cancer Inst., 44, 515 (effect of bovine enterovirus-1 on Sarcoma-1); Shingu et al., (1991) J. General Virology, 72, 2031 (effect of bovine enterovirus, MZ-468, on F-647a leukemia cells); Suskind et al., (1957) PSEBM, 94, 309 (effect of Coxsackie B3 virus on HeLa tumor cells); Rukavishnikova et al., (1976) Acta Virol., 20, 387 (effect of influenza A strain on ascites tumor).
The earliest references described partial tumor regression in patients treated with live attenuated viral vaccine with the aim to vaccinate them against smallpox or rabies. See DePace, N. G. (1912) Ginecologia, 9, 82–88; Salmon, P. & Baix (1922) Compt. Rend. Soc. Biol., 86, 819–820. Partial regression of tumors and regression of leukemias have also been noted during naturally occurring measles infections. See Pasquinucci, G. (1971) Lancet, 1, 136; Gross, S. (1971) Lancet, 1, 397–398; Bluming, A. Z. and Ziegler, J. L. (1971) Lancet, 2, 105–106. In one study of 90 cancer patients intentionally infected with live mumps virus, partial tumor regression was noted in 79 cases. See Asada (1974) Cancer, 34, 1907–1928. Serious sequelae of infection with these human pathogens, however, is of major concern. Furthermore, the mechanism of any anti-cancer effect was never fully explored by the investigators. All of the effects noted upon exposure to those viruses were also temporary.
3. NDV Effect on Cancer
Newcastle Disease Virus (“NDV”) is a member of the Paramyxovirus family. The natural hosts for NDV are chickens and other birds. NDV typically binds to certain molecules on the surface of animal host cells, fuses with the cell surface, and injects its genetic material into the host. Once inside, the viral genes direct the host cell to make copies of the virus. These copies of NDV are then released to infect other cells, which in turn destroy the host cell. Unlike some viruses, NDV is not known to cause any serious human disease. Unlike many other kinds of viruses (e.g., herpes, hepatitis, HIV), the Paramyxoviruses do not interfere with the host cell genes, and are not known to be carcinogenic.
Temporary regression of tumors has been reported in a small number of patients exposed to NDV, all of whom eventually succumbed to their cancers. See, Csatary, L. K. (1971) Lancet, 2, 825. Csatary noted the regression of a gastrointestinal cancer in a chicken farmer during an epidemic of Newcastle disease in his chickens. In a similar anecdotal report, Cassel, W. A. and Garrett, R. E. (1965) Cancer, 18, 863–868, noted regression of primary cervical cancer, which had spread to the lymph nodes, in a patient following injection of NDV into the cervical tumor. Since the mechanism of the observed tumoricidal activity was thought to be immunologic, no work was carried out to address direct tumor cytotoxicity of the virus. Instead, efforts focused upon the immuno-modulating effects of NDV. See, for example, Murray, D. R., Cassel, W. A., Torbin, A. H., Olkowski, Z. L., & Moore, M. E. (1977) Cancer, 40, 680; Cassel, W. A., Murray, D. R., & Phillips, H. S. (1983) Cancer, 52, 856; Bohle, W., Schlag, P., Liebrich, W., Hohenberger, P., Manasterski, M., Möller, P., and Schirrmacher, V. (1990) Cancer, 66, 1517–1523.
4. Delivery of Genes to Cancer Cells
Current approaches for delivery of genetic material into cells include the use of retrovirus vectors. See, e.g., Miller et al., (1992) Nature, 357, 455. The retrovirus delivers negatively-stranded RNA and the reverse transcriptase enzyme to produce a positive strand DNA. There are disadvantages in using retroviruses because the viruses are rendered incapable of producing progeny viruses, i.e., virus amplification cannot take place. Also, the use of retroviruses to deliver genetic material to cancer cells is not desirable because retroviral vectors tend to infect tumor cells at a relatively low percentage, thereby precluding efficient in-situ transfer of the desired genetic material into the tumor site. Furthermore, production of the gene of interest delivered by the retrovirus occurs at a rate determined by the cell cycle of the host cell which can severely limit the amount of gene product being translated.
The use of certain other viruses as recombinant vehicles for expression of genetic material has been described, for instance, vaccinia [Ramshaw et al., (1992) Immunological Reviews, 127, 157], adenovirus [Bett et al., (1993) J. Virology, 67, 5911; Natuk et al., (1992) Proc. Natl. Acad. Sci., 89, 7777; Chengalvala et al., Vaccine, 9, 485; Berkner, (1988) BioTechniques, 6, 616], and influenza virus [Li et al., Proc. Natl. Acad. Sci., 90, 5214]. See also, generally, Lyerly et al., (1993) Arch. Surg., 128, 1197.